Identifying celiac disease-related chemicals by transcriptome-wide association study and chemical-gene interaction analyses

Abstract

Celiac disease (CeD) is one of the most common intestinal inflammatory diseases, and its incidence and prevalence have increased over time. CeD affects multiple organs and systems in the body, and environmental factors play a key role in its complex pathogenesis. Although gluten exposure is known to be the causative agent, many unknown environmental factors can trigger or exacerbate CeD. In this study, we investigated the influence of genetic and environmental factors on CeD. Data from a CeD genome-wide association study that included 12,041 CeD cases and 12,228 controls were used to conduct a transcriptome-wide association study (TWAS) using FUSION software. Gene expression reference data were obtained for the small intestine, whole blood, peripheral blood, and lymphocytes. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses using the significant genes identified by the TWAS and conducted a protein–protein interaction network analysis based on the STRING database to detect the function of TWAS-identified genes for CeD. We also performed a chemical-related gene set enrichment analysis (CGSEA) using the TWAS-identified genes to test the relationships between chemicals and CeD. The TWAS identified 8,692 genes, including 101 significant genes (padjusted < 0.05). The CGSEA identified 2,559 chemicals, including 178 chemicals that were significantly correlated with CeD. This study performed a TWAS (for genetic factors) and CGSEA (for environmental factors) and identified several CeD-associated genes and chemicals. The findings expand our understanding of the genetic and environmental factors related to immune-mediated diseases.